Project Summary The goal of this NIH K99/R00 Pathway to Independence Award is to establish myself as an independent investigator in the field of metabolic imaging of gliomas. My research plan leverages my existing knowledge of cancer metabolism with new training and experience in glioma research, specifically as it pertains to sex differences in glioma tumorigenesis. Specifically, I will define how interactions between sex and common glioma driver mutations as regulators of glucose metabolism impact on glioma phenotype and to determine what the developmental origins are for sex differences in glucose metabolism. After having received my undergraduate degree from Cornell University, I matriculated to the Medical Scientist Training Program at Washington University. My thesis focused on prostate neuroendocrine (NE) cancer metabolism, integrating expression profiling and analytical chemistry techniques to identify enriched metabolic features of high grade NE cancers. When I returned to medical training, my clinical interests focused on diagnostic radiology. As a future physician-scientist, I felt that a research career in oncologic imaging would represent an ideal combination of my research and clinical interests. My interest in imaging research led me to stay at the Mallinckrodt Institute of Radiology at Washington University in St. Louis for training in a clinical diagnostic radiology residency program at Washington University. Following residency, I trained in a one year clinical Body MRI fellowship with a focus on oncologic imaging. During this training, I developed an interest in merging molecular imaging and cancer metabolism to identify new ways to stratify cancer patients and develop new treatment options for them. To date, my clinical training has provided a broad understanding of anatomic imaging techniques. On the other hand, my research training has helped establish a framework to understand cancer metabolism and the techniques used to study it. The goal of the next phase of my career is to develop a bridge between these two areas, developing expertise in brain tumor biology and small animal imaging to understand mechanisms underlying sex differences in brain tumorigenesis and metabolism. I have developed a training plan that culls the strengths of the Department of Radiology and the Siteman Cancer Center at Washington University to supply the necessary infrastructure of expertise and advanced technologies. For the K99 portion of my award, I will be housed in the laboratory of my mentor, Dr. Joshua Rubin, an expert in the field of sex differences in cancer. There, I will gain experience in the theory and techniques required to study brain tumor biology. This will be supplemented with coursework, seminars, and meetings to enhance my training that will provide a solid foundation for a future career that integrates cancer metabolism and imaging. I will also engage in didactic training in the design of translational research through the Institute of Clinical and Translational Sciences through Washington University in preparation for future projects that translate my basic science discoveries to the clinical setting. I will transition to an independent lab in the R00 phase where I will bring together novel methods and biological insights into tumor metabolism. This research proposal builds upon an emerging paradigm in the field of oncology. In many cancers throughout the human body, males not only have a higher incidence of malignancy than females, but they also do worse characterized by shorter relapse times and shorter overall survival. This is particularly true for glioblastoma multiforme (GBM), an extraordinarily aggressive glioma with dismal prognosis. Although the mechanisms underlying this phenomenon remain to be elucidated, I propose that inherent sex differences in glucose metabolism may begin to explain these observed phenomena. Under the instruction of Dr. Rubin, I will develop new animal models to identify mechanisms involved in sex differences in GBM. My long term goal is to understand the metabolic basis of why male cancer patients do worse than female cancer patients. This proposal will test the central hypothesis that sex differences in glucose metabolism underlie sex differences in GBM tumorigenesis. In the first aim, we will investigate the role of glycolysis- enhancing cancer mutations PTEN and EGFR in sex-specific tumorigenesis and metabolism using techniques developed in Dr. Rubin?s lab in combination with stable isotope labeling metabolism studies and PET imaging. In the second aim, we will identify the developmental origins of sex differences in glucose metabolism. We will use two animal models, novel to the cancer biology field, to identify the effects of sex chromosome complement and epigenetic effects of in utero exposure to sex hormones on astrocyte glucose metabolism. This research proposal is innovative because it will begin to identify sex-specific differences in cancer metabolism, an untouched field. The experiments outlined in this proposal will generate new insights into the mechanism behind sex differences in glucose metabolism and the impact of key drivers of the malignant phenotype. I anticipate that this will provide a platform for novel readily-translatable imaging methods and therapeutic approaches to not only brain tumors, but cancer in general.